Management of blood lipids in post-kidney transplant patients: a systematic review and network meta-analysis DOI Creative Commons

Bohan Luo,

Shan Zhong,

Xiaoxiao Wang

et al.

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: Oct. 8, 2024

Introduction The primary objective of this systematic review was to provide an overview the efficacy and safety various lipid-lowering therapies in patients post-kidney transplant (PKT), given limited existing literature. Considering restricted number available studies, work aimed summarize evidence regarding effectiveness different treatments PKT patients. effects therapeutic regimens on lipid levels were compared, their assessed, with heterogeneity treatment protocols acknowledged. Material Methods Randomized controlled trials investigating (DTRs) for regulating systematically retrieved from PubMed, Cochrane Library, Embase, inception March 2024. Literature quality assessed employing risk bias assessment tool. Data analysis graphical representation performed RevMan5.3 Stata 20.0 . surface under cumulative ranking area (SUCRA) compared DTRs profiles, incidence adverse events, all-cause mortality Results Fifteen studies included, comprising 5,768 involving 9 regimens. results revealed that, changes high-density lipoprotein cholesterol (HDL-C), SUCRA rankings highest lowest among receiving statins + ezetimibe (70%), placebo (61.5%), fibrates (57.2%), (44.1%), fish oil (17.3%). Regarding low-DL-C (LDL-C), (68.2%), (67.5%), (53.4%), (34.5%), (26.5%). For change total (TC) levels, a network meta-analysis (NMA) that DTRs, TC (97.6%), proprotein convertase subtilisin/kexin type inhibitors (PCSK9 inhibitors) (74.3%), (64.3%), (61.6%), (47.2%), (31.6%), calcineurin phosphatase (11.9%), immunosuppressants (11.4%). triglyceride (TG) NMA showed TG (99.9%), (68.9%), PCSK9 (66.6%), (55.1%), (49.2%), (45.0%), (7.8%), (7.6%). occurrence kidney failure, reducing failure (69.0%), (63.0%), steroids (51.8%), (27.1%), (22.5%). mortality, (90.5%), (55.8%), (3.7%). Conclusion In patients, combination therapy demonstrated notable advantages higher effectiveness. exhibited greater events rates safety.

Language: Английский

Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution DOI Creative Commons
Manish K. Yadav, Parishmita Sarma, Jagannath Maharana

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 2, 2024

Abstract The Hydroxycarboxylic acid receptor 2 (HCA2), also known as the niacin or GPR109A, is a prototypical GPCR that plays central role in inhibition of lipolytic and atherogenic activities. Its activation results vasodilation linked to side-effect flushing associated with dyslipidemia drugs such niacin. GPR109A continues be target for developing potential therapeutics minimized response. Here, we present cryo-EM structures complex drugs, acipimox, non-flushing agonists, MK6892 GSK256073, recently approved psoriasis drug, monomethyl fumarate (MMF). These elucidate binding mechanism molecular basis activation, insights into biased signaling elicited by some agonists. structural framework allows us engineer mutants exhibit G-protein bias, therefore, our study may help structure-guided drug discovery efforts targeting this receptor.

Language: Английский

Citations

9
Insights into the Activation Mechanism of HCA1, HCA2, and HCA3 DOI Creative Commons
Jiening Wang, Yuxia Qian, Zhen Han

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 12, 2025

Hydroxy-carboxylic acid receptors HCA1, HCA2, and HCA3 can be activated by important intermediates of energy metabolism. Despite the research focusing on its clinical application has been limited adverse effects. Therefore, role HCA1 as a promising target for treatment lipolysis warrants further exploration. As HCAs exhibit high similarity when with diverse selective agonists, conserved yet unique activation mechanism remains undisclosed. Herein, we unveil cryo-electron microscopy structures 3,5-DHBA-HCA1-Gi signaling complex, acifran- MK6892-bound HCA2-Gi complexes, acifran-HCA3-Gi complex. Comparative analysis across reveals key residues in contributing to stabilization ligand-binding pocket. Furthermore, chimeric complexes mutational analyses identify that are pivotal HCA2 selectivity. Our findings elucidate critical structural insights into mechanisms ligand recognition within broaden our comprehension specificity binding HCA family.

Language: Английский

Citations

0
Structures of G-protein coupled receptor HCAR1 in complex with Gi1 protein reveal the mechanistic basis for ligand recognition and agonist selectivity DOI Creative Commons
Xin Pan, Fang Ye,

Peiruo Ning

et al.

PLoS Biology, Journal Year: 2025, Volume and Issue: 23(4), P. e3003126 - e3003126

Published: April 15, 2025

Hydroxycarboxylic acid receptor 1 (HCAR1), also known as lactate or GPR81, is a class A G-protein-coupled with key roles in regulating lipid metabolism, neuroprotection, angiogenesis, cardiovascular function, and inflammatory response humans. HCAR1 highly expressed numerous types of cancer cells, where it participates controlling cell metabolism defense mechanisms, rendering an appealing target for therapy. However, the molecular basis HCAR1-mediated signaling remains poorly understood. Here, we report four cryo-EM structures human HCAR2 complex Gi1 protein, which binds to subtype-specific agonist CHBA (3.16 Å) apo form (3.36 Å), agonists MK-1903 (2.68 SCH900271 (3.06 Å). Combined mutagenesis cellular functional assays, elucidate mechanisms underlying ligand recognition, activation, G protein coupling HCAR1. More importantly, residues that determine selectivity between are clarified. On this basis, further summarize structural features match orthosteric pockets HCAR2. These insights anticipated greatly accelerate development novel HCAR1-targeted drugs, offering promising avenue treatment various diseases.

Language: Английский

Citations

0
Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode DOI Creative Commons

Aslihan Shenol,

Ricardo Tenente, Michael Lückmann

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 25, 2024

Abstract A surprisingly clear picture of the allosteric mechanism connecting G protein-coupled receptor agonists with protein binding—and back – is revealed by a puzzle thirty novel 3D structures hydroxycarboxylic acid 2 (HCAR2) in complex eight different orthosteric and single agonist. HCAR2 sensor β-hydroxybutyrate, niacin certain anti-inflammatory drugs. Surprisingly, without on-target side effects bound very similarly completely occluded binding site. Thus, despite many we are still left pertinent need to understand molecular dynamics this similar systems.

Language: Английский

Citations

2
Association between dietary intake of niacin and stroke in the US residents: evidence from national health and nutrition examination survey (NHANES) 1999–2018 DOI Creative Commons

Jie-Yu Qiu,

Wenhui Zhang, Zhu Xiao-ming

et al.

Frontiers in Nutrition, Journal Year: 2024, Volume and Issue: 11

Published: July 19, 2024

Objective This study aims to explore the association between niacin intake and stroke within a diverse, multi-ethnic population. Methods A stringent set of inclusion exclusion criteria led enrollment 39,721 participants from National Health Nutrition Examination Survey (NHANES). Two interviews were conducted recall dietary intake, USDA’s Food Nutrient Database for Dietary Studies (FNDDS) was utilized calculate based on results. Weighted multivariate logistic regression employed examine correlation stroke, with simultaneous exploration potential nonlinear relationships using restricted cubic spline (RCS) regression. Results comprehensive analysis baseline data revealed that patients history had lower levels. Both RCS indicated negative stroke. The dose-response relationship exhibited non-linear pattern range intake. Prior inflection point (21.8 mg) in risk, there exists marked decline risk as increases. Following point, deceleration decreasing trend increasing becomes evident. points exhibit variations across diverse populations. Conclusion investigation establishes broader American

Language: Английский

Citations

1
Ligand recognition and activation mechanism of the alicarboxylic acid receptors DOI
Yanru Liu,

Ziwei Zhou,

Fenghui Guan

et al.

Journal of Molecular Biology, Journal Year: 2024, Volume and Issue: unknown, P. 168795 - 168795

Published: Sept. 1, 2024

Language: Английский

Citations

1
Management of blood lipids in post-kidney transplant patients: a systematic review and network meta-analysis DOI Creative Commons

Bohan Luo,

Shan Zhong,

Xiaoxiao Wang

et al.

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: Oct. 8, 2024

Introduction The primary objective of this systematic review was to provide an overview the efficacy and safety various lipid-lowering therapies in patients post-kidney transplant (PKT), given limited existing literature. Considering restricted number available studies, work aimed summarize evidence regarding effectiveness different treatments PKT patients. effects therapeutic regimens on lipid levels were compared, their assessed, with heterogeneity treatment protocols acknowledged. Material Methods Randomized controlled trials investigating (DTRs) for regulating systematically retrieved from PubMed, Cochrane Library, Embase, inception March 2024. Literature quality assessed employing risk bias assessment tool. Data analysis graphical representation performed RevMan5.3 Stata 20.0 . surface under cumulative ranking area (SUCRA) compared DTRs profiles, incidence adverse events, all-cause mortality Results Fifteen studies included, comprising 5,768 involving 9 regimens. results revealed that, changes high-density lipoprotein cholesterol (HDL-C), SUCRA rankings highest lowest among receiving statins + ezetimibe (70%), placebo (61.5%), fibrates (57.2%), (44.1%), fish oil (17.3%). Regarding low-DL-C (LDL-C), (68.2%), (67.5%), (53.4%), (34.5%), (26.5%). For change total (TC) levels, a network meta-analysis (NMA) that DTRs, TC (97.6%), proprotein convertase subtilisin/kexin type inhibitors (PCSK9 inhibitors) (74.3%), (64.3%), (61.6%), (47.2%), (31.6%), calcineurin phosphatase (11.9%), immunosuppressants (11.4%). triglyceride (TG) NMA showed TG (99.9%), (68.9%), PCSK9 (66.6%), (55.1%), (49.2%), (45.0%), (7.8%), (7.6%). occurrence kidney failure, reducing failure (69.0%), (63.0%), steroids (51.8%), (27.1%), (22.5%). mortality, (90.5%), (55.8%), (3.7%). Conclusion In patients, combination therapy demonstrated notable advantages higher effectiveness. exhibited greater events rates safety.

Language: Английский

Citations

0